G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons.

Lingli Liang,Jian-Yuan Zhao,Kai Mo,Xiyao Gu,Xuerong Miao,Alex Bekker,Jifang Xiao,Shaogen Wu,Brianna Marie Lutz,Yuan-Xiang Tao,Jun Zhang

doi:10.1038/srep37704

Lingli Liang, Jian-Yuan Zhao + Show 9 more

Open Access

https://doi.org/10.1038/srep37704

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Abstract

Nerve injury-induced downregulation of voltage-gated potassium channel subunit Kcna2 in the dorsal root ganglion (DRG) is critical for DRG neuronal excitability and neuropathic pain genesis. However, how nerve injury causes this downregulation is still elusive. Euchromatic histone-lysine N-methyltransferase 2, also known as G9a, methylates histone H3 on lysine residue 9 to predominantly produce a dynamic histone dimethylation, resulting in condensed chromatin and gene transcriptional repression. We showed here that blocking nerve injury-induced increase in G9a rescued Kcna2 mRNA and protein expression in the axotomized DRG and attenuated the development of nerve injury-induced pain hypersensitivity. Mimicking this increase decreased Kcna2 mRNA and protein expression, reduced Kv current, and increased excitability in the DRG neurons and led to spinal cord central sensitization and neuropathic pain-like symptoms. G9a mRNA is co-localized with Kcna2 mRNA in the DRG neurons. These findings indicate that G9a contributes to neuropathic pain development through epigenetic silencing of Kcna2 in the axotomized DRG.

Highlights

12% of dorsal root ganglion (DRG) neurons (120 of 989) were labeled for G9a, of which about 31% of the G9a-labeled neurons were positive for calcitonin gene-related peptide (CGRP, a marker for small DRG peptidergic neurons), 29% for isolectin B4 (IB4, a marker for small non-peptidergic neurons), and 43% for neurofilament-200 (NF200, a marker for medium/large cells and myelinated A-fibers) (Fig. 1A)
Our findings indicate that induction of G9a expression and increased level of H3K9me[2] occurs exclusively in the axotomized DRG neurons and in response to peripheral nerve injury
This study provides the first evidence to our knowledge that nerve injury-induced increases in G9a and its catalyzed repressive marker H3K9me[2] are responsible for epigenetic silencing of Kcna[2] in the axotomized DRG neurons

Summary

Introduction

A recent study showed an involvement of G9a in nerve injury-induced downregulation of some DRG potassium channel genes[15], whether and how G9a regulates Kcna[2], a highly expressed potassium channel in the DRG4,5, under neuropathic pain conditions is unknown. We report that peripheral nerve injury increases the expression of G9a and H3K9me[2] in the axotomized DRG neurons. These increases contribute to neuropathic pain development through epigenetic silencing of DRG Kcna[2]

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